Project Summary/Abstract Substance use (SU) negatively affects the risk, management, progression, and outcomes of chronic disease and contributes to socio-economic and racial/ethnic disparities. Prevalence rates of medical conditions among patients with versus those without substance abuse disorders (SUDs) support this thesis. Furthermore, risks are exacerbated among those at risk for or who already have chronic medical conditions, such as people living with HIV. Though linkages between SU and disease are well documented, physiological mechanisms underlying linkages are poorly understood, largely because the literature is based on studies that use cross-sectional designs that do not allow for causal interpretations. Studies using experimental designs are needed to understand mechanisms that link SU and disease and to inform the development of targeted prevention and intervention efforts to reduce risks. We propose to establish a COBRE Center for Addiction and Disease Risk Exacerbation (CADRE) that will investigate mechanisms whereby SU impacts disease, using a combination of behavioral and physiological laboratory-based approaches across several substances of abuse. CADRE consists of four thematically and technically-linked research projects (RPs) led by an interdisciplinary group of junior faculty. Monnig will examine effects of HIV and alcohol on markers of microbial translocation, monosite activation, cytokine response, tryptophan degradation and MRI measures of inflammation. Haass-Koffler will examine the initial efficacy of oxytocin as a potential pharmacotherapy for OUD targeting stress in opioid relapse. Cioe will study effects of e-cigarettes on combustible cigarette smoking, biomarkers of smoking-related cardiac and pulmonary health, and carcinogen exposure in smokers with HIV. Aston examines effects of cannabis on RA pain, affect, and inflammation, and investigates whether effects of cannabis on pain and affect are mediated via effects of cannabis on inflammatory biomarkers. An Administrative Core will provide organizational structure, state-of-the-art mentoring, a pilot program, support diversity and health disparities work, and lead evaluation. A Clinical Laboratory Core will facilitate goals of the RPs and pilot projects, and benefit the broader Brown community by providing infrastructure and resources in the service of developing and sustaining a multi- disciplinary center. It will maximize efficiency and cost-effectiveness of this COBRE by creating linkages between CADRE RPs and other COBREs, and will create a center-wide data base of risk factors associated with development and progression of SUDs and chronic disease, available to CADRE Project Leaders (PLs) and others engaged in relevant research. PLs and pilot PLs will benefit from interdisciplinary faculty mentors who will provide guidance on research, publication, and grant preparation. The basic tenet of the proposed COBRE CADRE is that innovative interdisciplinary translational research, conducted across multiple levels of analysis, and focused on related questions using common resources and learning experiences, can not only contribute new knowledge, but also serves as the nexus and path toward independence for the next generation of scientists.